Powders and granules can be used as dosage forms in their own right, but by far the greatest use of granules and powders in the pharmaceutical industry is as an intermediate during the manufacture of compressed tablets. Such products begin with the starting materials – the active pharmaceutical ingredient, API, and various excipients. In addition to transporting the active drug to the area in the body where the drug is intended to exert its action, excipients play an important part in the manufacturing process. They may also be important for keeping the drug from being released too early when ingested – in places where it could damage tender tissue and create gastric irritation or stomach upset. Excipients include diluents or fillers, binders, disintegrants, lubricants, colouring agents and preservatives. Last, but not least, some excipients are used simply to make the product taste and look better. This improves patient compliance, especially in children. Although technically "inactive" in a therapeutic sense, pharmaceutical excipients are critical and essential components of a modern drug product. In many products, excipients make up the bulk of the total dosage form.

Each of the starting materials, i.e., API and excipients may be supplied initially as powders with different particle sizes and densities, and the first task in the manufacturing process is to mix them so that they can be fed forward to a granulation process. Granulation is usually required to increase the average particle size of the powders so as to create material that freely flows into the tablet making machinery. The granulation process at best will create a well-mixed material but it requires careful control on the part of the manufacturer to ensure good mixing, and often some separation of the different materials can occur, on account of the different particle sizes, shapes and densities of the starting materials. Indeed, even before the granulation process takes place, some separation or segregation of the different materials can occur. This is particularly the case if the mixed materials have to be conveyed a significant distance between the mixing stage and the granulation stage, e.g. by a pneumatic or vacuum system.

Vacuum-conveying technology is commonly used in the pharmaceutical industry to move materials through the processing line, blend ingredients in various solutions, and handle tablets. Because it is an enclosed system, vacuum conveying is safe, hygienic, and the preferred solution for many applications. The vacuum conveying of powders and granules, however, must be performed well to avoid segregation, the separation of ingredients that results in an uneven mixture.

Segregation – a costly problem Segregation during the conveying of powders is a significant problem for the pharmaceutical industry. Indeed, particle segregation is a common problem in many bulk storage systems and its presence creates serious quality control issues. Segregation creates inconsistent batches that can cause dosage variations in pharmaceuticals, significant weight and flavour variations in packaged foods and gas flow problems in chemical reactors.

There are more than a dozen easily identifiable segregation mechanisms that result in out-of-spec products, but the five most common segregation mechanisms -- sifting, angle of repose, fines fluidization, air currents and chute trajectory – are responsible for more than 80 percent of segregation problems in solids handling and storage systems.

Sifting segregation

This is mostly likely to occur in a mixture containing free-flowing particles of significant size variation – typically differences in the mean diameter of 3 times or more. Inter-particle motion, often brought about through vibration, causes the finer components to sift through coarse components. All bins, batch blenders and chutes have the potential for sifting segregation problems. Because it uses an air stream to move particles, vacuum conveying also presents the risk that ingredients will separate through sifting. Small particles will pass through the mixture of larger particles. Dense particles will drop below less dense particles, and stratified flow can occur.

Angle of repose segregation

The angle of repose of a granular material is the steepest angle of descent or dip relative to the horizontal plane to which a material can be piled without slumping. At this angle, the material on the slope face is on the verge of sliding. The angle of repose can range from 0° to 90°. The morphology of the material affects the angle of repose; smooth, rounded grains cannot be piled as steeply as can rough, interlocking grains. The angle of repose can also be affected by additions of solvents; if a small amount of water is able to bridge the gaps between particles, electrostatic attraction of the water to mineral surfaces will increase the angle of repose. Angle of repose segregation occurs when particles deposited with greater angles of repose form a steep pile under the deposition point while the ones with lower angle of repose roll away from that point.

A mixture containing components that are cohesive or rough-surfaced are particularly prone to angle-of-repose segregation. Rotating shell-type blenders, stock piles and bins are susceptible to this mechanism.

Fluidization segregation

Fluidization segregation can occur when a mixture contains a large portion of light or fluffy free-flowing, fine component, enough to form a layer, and smaller portion of a relatively coarse, heavier component. The larger component easily penetrates the fluidized fines, pushing the fines layer to the top of the bin or vessel. Fluidization is especially active in air blenders, high-speed ribbon blenders, bins and piles.

Air current segregation

The finer particles in a mix are susceptible to be airborne in the presence of airflow. These very fine particles migrate to the walls of a vessel wall or toward a dust collection system. If the fines are a minor component of the mixture or are cohesive, migration can be significant.

Chute trajectory segregation

This type of segregation occurs as a result of particles having different coefficients of friction and results in different discharge trajectories as the mix slides down a chute. It can occur in the feed hopper of a tablet making machine. High friction coefficient materials usually contain fine particles and slide more slowly down a chute than low friction materials. This results in different discharge trajectories. Particles with high friction coefficients show lower discharge angles the end close to the chute, whereas the trajectory of particles with low coefficients of friction deviate further away from the chute.

Many pharmaceutical products depend on an accurate powder-to-powder ratio, and end-product quality is in jeopardy if segregation is not mitigated. The problem should be addressed in advance because much raw material may be wasted even if the incorrect mixture is detected before end processing.

Solutions to powder segregation

There are some simple, practical steps that can help to reduce these segregation mechanisms. The following are suggested modifications of equipment or operating procedures, both of which do not usually require large capital expenditures.

DO use a bin with tall cylindrical section that provides flow at the walls.

DO use a mixing device at the centre for charging a multiple-outlet bin. This will create uniform, symmetric segregation.

DO proportion and mix badly segregated materials just before processing using as little surge capacity as possible.

DO use a tangential entry for pneumatically conveyed fluidizable solids or install a cyclone at the bin top that uses a deflection plate.

DO use inclined open chutes to decrease air entrainment in ascending solids. This not only reduces fluidization entrainment, it also reduces dusting.

DO premix liquid with coarser particles before adding finer components if sifting or angle of repose segregation is likely to be present.

DO use blenders that remix top-to-bottom during hopper discharge or use static stream blenders below belt discharge points to remix segregated solids.

DON’T split material from a belt conveyor into various bins since the belt may segregate the materials.

DON’T use a non-symmetrical, multiple-outlet bin.

DON’T use a uniform velocity mass-flow bin to cure fluidization-type segregation. It will only make it worse.

DON’T use freefall chutes to transfer materials with different friction angles unless there is a mixing device downstream.

DON’T charge a mixture of fine fluidizable powder and non-fluidizable coarse particles from a pneumatic conveying line using a vertical downspout.

Lean-phase versus dense-phase conveying Segregation is not exclusively a powder- and bulk-conveying problem. It can occur when a product is transferred from a mixer to a feeder or during mix discharge at the end of the conveying line, where heavier materials drop to the bottom of the mixer. But manufacturers can take steps to optimize the conveying process.

With pneumatic or vacuum conveying, processes known as lean-phase conveying and dense-phase conveying can occur. During lean-phase conveying, a great amount of air is mixed with a small quantity of powder, the outcome of which is which high air velocity and high powder velocity. In lean-phase conveying, the volume and speed of air are high enough to keep particles continuously moving in suspension. These factors also increase the likelihood of segregation because light and less-dense particles flow faster than heavy and dense particles, which may lead especially to sifting or airborne segregation.

Dense-phase, or plug-phase flow conveying occurs at a slow speed. A low flow rate of air in the conveyer moves material in plugs separated by small distances. This conveying technique can create fluidization, which converts powdered material into a well-mixed fluid-like state. Sometimes used at the suction point and discharge point, fluidization lets air pass through porous materials. Fluidized material is moved in waves at a slower speed than the compressed air.

Dense-phase conveying maintains the desired ratio of the mixture much better than lean phase conveying. Air speed is not as high in dense-phase conveying as in lean-phase conveying, so that the separation or segregation resulting from particle-size and weight variation is lower.

Empirical testing improves quality and content Although segregation is a common problem with powders and granules, no universal solution exists for all materials or formulations. Each conveying application has to be considered in its own right. Dense-phase conveying is the best strategy to mitigate segregation, but it cannot be applied in every case. Different materials behave differently and should be tested and evaluated before the conveying process is adjusted. Likewise, different mixes of ingredients will require different adjustments to the conveying application.

Pharmaceutical companies test their mixes regularly to ensure consistent content and high product quality. The conveying line should also be assessed, to determine how process variables affect the transfer and segregation of material. For example, elements such as piping (e.g., pipe ends, bends, and sharp edges) may change the material’s flow characteristics and affect segregation. The whole conveyance system should therefore be assessed before developing a solution.

Developing the optimal solution New conveying products and systems will help pharmaceutical manufacturers reduce segregation. PIAB, a Swedish supplier of vacuum conveying equipment, is currently developing a constant-speed vacuum conveyor. Setting the vacuum pump that provides flow in the conveyor at a consistent speed may ensure that, regardless of the product being conveyed, segregation would be an easier problem to solve. Typical vacuum pumps are affected by the pressure drops that occur throughout a system, but the pump PIAB is developing compensates for pressure drops by changing the flow (i.e., speed).